The identification of the v-raf-1 oncogene from the defective retrovirus 3611-MSV has allowed the isolation of a new family of proto-oncogenes. The active homolog of v-raf, c-raf-1, is located at position p25 on chromosome 3 in man, a site that is frequently altered in a variety of neoplasia, including small cell lung carcinoma. Moreover, transforming versions of c-raf-1 have been identified in human stomach cancer and glioblastoma. Expression of c-raf-1 mRNA and protein in human lung carcinoma cell lines occurs at levels that are in excess of those found in NIH 3T3 cells transformed by c-raf MSV. To study the role of raf in lung carcinogenesis in vivo, we have developed an animal model where 90% of newborn mice treated transplacentally with ethylnitrosourea and promoted at birth with butylated hydroxytoluene develop lung tumors and lymphomas within 5 to 14 weeks. High c-raf-1 expression in tumors and established cell lines has been determined by Northern blot and immunoblotting analyses. DNA prepared from both lung tumors and lymphomas is transforming for NIH 3T3 cells as determined by DNA-transfection. The nature of the activated transforming DNA is currently being examined. Moreover, we have now defined conditions using growth modulators and hormones for the differential inhibition of raf-transformed, but not untransformed, control cell lines in vitro. These regimens are now being tested in our animal model system, in conjunction with vaccination experiments using purified raf protein, to examine their potential inhibitory actions on the development of these tumors.